Retinal Capillary Hemangioblastoma: A Comprehensive Review on Treatments

Abstract

Background

Retinal capillary hemangioblastoma (RCH) is a benign tumor that frequently appears as the first manifestation in patients with von Hippel-Lindau (VHL) disease, potentially resulting in significant vision loss. Thus, recognizing and managing it promptly is crucial.

Summary

New imaging techniques, including widefield optical coherence tomography (OCT) and OCT angiography, improve diagnostic accuracy and monitoring, facilitating early treatment and better prediction of visual outcomes. While traditional therapies such as laser photocoagulation, cryotherapy, and vascular endothelial growth factor inhibitors serve as the cornerstones of RCH therapy, new approaches, including tyrosine kinase inhibitors and hypoxia-inducible factor inhibitors, also exhibit promising results in treating resistant or recurrent tumors. Furthermore, genetic testing and counseling are beneficial for identifying patients linked to VHL disease, allowing early detection of systemic manifestations of this syndrome and enabling proper therapeutic management.

Key Messages

This review consolidates the epidemiology, pathophysiology, clinical imaging, diagnostic evaluation, and treatment of RCH, emphasizing new insights pertinent to clinical practice and patient care.

Introduction

Retinal capillary hemangioblastoma (RCH), also known as retinal capillary hemangioma, is a rare, highly vascular neoplasm of retinal tissue that may occur sporadically or as the earliest manifestation of von Hippel-Lindau disease (VHL), an inherited autosomal dominant. VHL disease has an incidence of approximately 1 in 36,000 live births [1]. RCH is the most common ocular feature of VHL, occurring in up to 77% of affected individuals, and may present in the peripheral retina, macula, and peripapillary region [2]. Peripheral tumors are often asymptomatic initially, whereas juxtapapillary or larger lesions can lead to significant visual impairment through exudation, epiretinal membrane formation, vitreous traction, or retinal detachment (RD) [3].

Diagnosis of VHL can be established based on the following clinical criteria: positive family history and presence of a central nervous system (CNS) hemangioblastoma, RCH, pheochromocytoma, or clear cell carcinoma. In the absence of a family history, the presence of two CNS hemangioblastoma, or two RCHs, or one CNS hemangioblastoma or one RCH accompanied by a visceral tumor, is diagnostic [4]. Early diagnosis and intervention are necessary to prevent irreversible ocular complications and to prompt systemic evaluation for VHL syndrome as it can be a life-threatening disease causing multiple visceral and CNS tumors. In the case of multiple RCHs or bilateral ocular tumors, the diagnosis of VHL is definite; however, up to 46% of cases with solitary RCH may have VHL disease, especially if diagnosed at a younger age [5].

Visual loss in RCH occurs via two principal mechanisms. Smaller tumors predominantly induce exudative RD or macular edema. Larger tumors promote epiretinal and vitreous fibrovascular proliferation, resulting in epiretinal membranes, vitreoretinal traction, and tractional, rhegmatogenous, or combined tractional-rhegmatogenous-exudative RD, the latter being particularly challenging to manage surgically [6]. Management of RCH is guided by tumor size, location, and associated complications. Small peripheral lesions may be observed or treated with laser photocoagulation or cryotherapy to induce regression. Medium-sized or juxtapapillary lesions may require photodynamic therapy (PDT), intravitreal anti-vascular endothelial growth factor (VEGF) agents, or plaque radiotherapy to control exudation and tumor growth. Complex or advanced RCHs, especially those associated with retinal traction or detachment, often necessitate surgical intervention, including pars plana vitrectomy (PPV), membrane peeling, endolaser photocoagulation, or tumor excision, to preserve or restore vision [3, 6]. Vitreous hemorrhage rarely occurs spontaneously in RCH but is a recognized sequela of ablative treatments. End-stage disease, however, may progress to neovascular glaucoma and phthisis bulbi. Recent advances in imaging, molecular diagnosis, and surgical techniques have improved outcomes for patients with RCH [4, 7]. This review provides an updated overview of RCH, focusing on clinical characteristics, diagnostic approaches, genetic testing, and current therapeutic strategies, including surgical management of complex lesions, to guide ophthalmologists in optimizing patient care.

Methods

This narrative review synthesizes current evidence on the pathophysiology, diagnosis, and management of RCH. For treatment-focused evidence, a comprehensive literature search was conducted in PubMed, Embase, and Scopus from inception to October 2025. The detailed search strategy is provided in the online supplementary material (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000550011). We prioritized original clinical studies (retrospective series, prospective cohorts, and clinical trials) reporting outcomes in eyes with RCH. Case reports, reviews, editorials, letters, and non-peer-reviewed sources were excluded to ensure robustness. Studies on non-ocular VHL manifestations or animal models were also excluded. References were screened by two authors independently, and discrepancies were resolved by consensus. Data were extracted and synthesized narratively due to heterogeneity in study design and interventions.

Pathophysiology

The VHL gene, located on chromosome 3p25-26 [8], encodes a tumor-suppressor protein (pVHL) that forms an E3 ubiquitin ligase complex with Elongin B, Elongin C, Cullin 2, and Ring Box Protein 1 (Rbx1) [9, 10] (Fig. 1). Under normoxic conditions, pVHL recognizes hydroxylated hypoxia-inducible factor (HIF)-1α and HIF-2α, targeting them for proteasomal degradation. In hypoxia or with VHL inactivation, HIF-α subunits accumulate, translocate to the nucleus, and transcriptionally activate genes including VEGF, PDGF, TGF, EPO, angiopoietin, and transferrin [11–13].

Fig. 1.

VHL-HIF pathway. The pVHL complex (via Elongin B/C, Cullin 2, Rbx1) binds hydroxylated HIF-1α (β-domain) and facilitates polyubiquitination (α-domain). Under normoxia, HIF-1α is degraded. In hypoxia or VHL mutation, HIF-1α accumulates and drives expression of VEGF, PDGF, EPO, and angiopoietin, promoting angiogenesis and tumor growth.

Loss of functional pVHL disrupts HIF regulation, leading to constitutive angiogenic signaling. This mechanism underlies RCH development and shares molecular features with CNS hemangioblastomas, particularly HIF-2α overexpression [9]. Figure 1 illustrates the pathway under normoxia and in VHL deficiency.

In summary, VHL loss stabilizes HIF, upregulates pro-angiogenic factors, and drives RCH formation. Understanding this axis is critical for targeted therapy development.

Diagnostic Approaches

Clinical findings are often pathognomonic, but multimodal imaging is essential for early detection and monitoring.

Fundus Photography

Ultra-widefield imaging via scanning laser ophthalmoscopy captures peripheral lesions invisible on routine exam and enables longitudinal monitoring [10]. A cohort study using ultra-widefield imaging identified peripheral RCH as the strongest predictor of post-treatment recurrence [14].

Fluorescein Angiography

RCH shows early hyperfluorescence and late leakage. Fluorescein angiography (FA) is critical for differentiating RCH from mimics (e.g., Coats disease and vasoproliferative tumor) [15]. Widefield FA (WF-FA) detects 67% more lesions than funduscopy. A retrospective study using ultra-WF-FA showed that only 33% of FA-detected lesions are visible (Fig. 2, 3) [16]. Oral fluorescein enables FA in pediatric patients without IV access [17].

Fig. 2.

Multimodal imaging of peripheral RCH in VHL. a Color fundus: tortuous feeder/draining vessels, orange nodular RCH, exudation. b Widefield FA: intense leakage, peripheral non-perfusion. c OCT: intraretinal/subretinal fluid, preretinal membrane.

Fig. 3.

Isolated peripapillary RCH. a Color fundus: peripapillary RCH lesion with adjacent exudation. b FA of the same eye showing leakage.

Indocyanine Green Angiography

Indocyanine green angiography is not primary for RCH diagnosis but aids in distinguishing juxtapapillary RCH from peripapillary choroidal neovascularization. It also guides PDT [18].

Ultrasonography

B-scan ultrasound measures large RCH (>4 mm) and assesses complications (e.g., RD) when media opacity (cataract, hemorrhage) obscures fundus view [19].

Optical Coherence Tomography

High-resolution optical coherence tomography (OCT) reveals hyperreflective inner retinal mass with posterior shadowing and intraretinal/subretinal fluid. Widefield OCT enables single-scan peripheral imaging, facilitating early detection in VHL surveillance [20, 21].

Optical Coherence Tomography Angiography

Optical coherence tomography angiography (OCTA) non-invasively maps intralesional flow, showing dense vascular networks with terminal budding. Feeder/draining vessels are visible in peripheral RCH (superficial slab) but absent in juxtapapillary RCH [22–24]. OCTA is especially helpful for detecting small, early RCHs that may not be evident on clinical exams or FA [25]. Widefield OCTA detects lesions missed on ophthalmoscopy, especially small, flat, or masked RCH [26]. A mechanistic model integrating OCTA and pathology suggests angiogenesis initiates at ∼200 µm tumor diameter, followed by stable vessel maturation [27]. OCTA guides navigated laser photocoagulation for precise early treatment [25].

Multimodal Imaging

Multimodal Imaging plays a key role in the diagnosis of retinal hemangioblastoma, especially the juxtapapillary lesions. The intraretinal location of these exophytic lesions, typically involving the outer retinal layers, may make precise diagnosis challenging as they lack the characteristic orange-red color. These lesions reveal nodular outer retinal thickening with shadowing and intra/subretinal fluid on OCT, hypoautofluorescence, hypervascularity of middle and outer retinal layers on OCTA, with early hyperfluorescence and late leakage on FA [28].

Genetic Testing

Genetic confirmation of VHL mutation is definitive for VHL disease. Testing is indicated in RCH patients, especially under 40 years, due to a 45% VHL risk in young solitary RCH versus 0.5% in those over 60 years [5].

Testing methods include Sanger sequencing to detect single-nucleotide variants and indels, multiple ligation-dependent probe amplification for large deletions, and whole-exome sequencing if initial tests are negative to assess single-nucleotide variants, indels less than 50 bp, and structural variants 50 bp or larger [29, 30]. Genotype-phenotype correlations are inconsistent. A meta-analysis identified mutation hot spots R167Q/W, Y98H, R238W, and S65l [31]. A TGFBI p.R124H variant was associated with RCH and granular corneal dystrophy type II in one whole-exome sequencing study [30]. More studies are needed to establish the exact relationship between these genetic abnormalities and the increased risk of RCH.

Management Strategies

Management of retinal hemangioblastoma has evolved to incorporate both long-established local therapies and newer systemic approaches. Treatment is typically indicated for any RCH lesion, especially those causing visual symptoms or macular-threatening exudation [32].

Observation

Some authors suggest that asymptomatic, small peripheral tumors may be monitored regularly without immediate intervention. However, observation carries the risk of tumor growth and secondary effects (exudation can threaten the fovea even from peripheral lesions). Therefore, most experts advocate treating RCHs once identified, unless the lesion is truly quiescent and far from the posterior pole or treatment burden is high (e.g., peripapillary lesions) [33].

Laser Photocoagulation

Laser treatment is an effective modality for small tumors (<3 mm) located outside the macula. Laser therapy induces tumor regression by occluding feeder vessels.

Outcomes for laser are very favorable in appropriately sized lesions. A large retrospective series (74 patients, 304 tumors) reported that 97% of RCHs were successfully inactivated by laser alone. Even among larger lesions (>1 DD), laser monotherapy achieved inactivation in approximately 73%. When combined with adjunct cryotherapy for the partial responders, overall tumor control increased to 99% [34]. A recent real-world report of a retrospective interventional cohort of eyes with VHL-related RCH showed tumor regression with laser photocoagulation alone in 37% of 27 eyes. Worse visual outcomes were observed in eyes with lower BCVA at presentation, larger tumor size, or those that required surgical intervention [35].

Cryotherapy

Trans-scleral cryotherapy is another well-established local therapy, particularly for larger peripheral RCHs (approximately 1.5–4 mm) or those with extensive exudation or subretinal fluid and vitreoretinal traction. This method involves freezing the lesion via an external probe, causing endothelial damage and tumor infarction. It is often performed under indirect ophthalmoscopy guidance. Cryotherapy can achieve tumor regression in most cases, although the success is somewhat dependent on the tumor size. A study by Kim et al. [36] found that 90% of small RCHs responded to cryotherapy, compared to 67% of larger lesions.

PDT and Transpupillary Thermotherapy

For the selected cases (particularly juxtapapillary RCHs), PDT with verteporfin has been used to induce thrombosis of the tumor vasculature. PDT involves intravenous verteporfin followed by laser activation (∼689 nm), which generates singlet oxygen and damages endothelial cells. Small case series have shown that PDT can cause the regression of RCH and decrease exudation, especially in lesions where thermal laser would be risky (e.g., at the disc) [37, 38]. However, RCHs often require multiple PDT sessions, and results are variable. So, PDT is generally considered a second-line adjunctive therapy. Transpupillary thermotherapy (TTT), a type of long-duration infrared laser treatment, has also been tried for moderate-sized RCHs. In a study by Kim et al. [36], TTT alone was applied to tumors between 0.5 and 3 mm, achieving a 70% success rate in regression. ICG-enhanced TTT is used for treatment-naïve juxtapapillary RCH, and results in 75% tumor regression with reduction of subretinal fluid [39].

Anti-VEGF Therapy

VEGF is upregulated in RCH (as part of the VHL-HIF pathway), so anti-VEGF agents have been explored to treat exudative complications. Intravitreal injections of bevacizumab or ranibizumab are commonly used as adjunct therapy for RCH-associated macular edema and exudation.

They often lead to a reduction of subretinal fluid and retinal thickening, improving or stabilizing vision. There is also anecdotal evidence that repeated anti-VEGF injections can lead to visual improvement in some cases, particularly in patients with smaller lesions and less exudation. Nevertheless, changes in lesion size and exudation were variable, and 4 of 5 patients gained minimal beneficial effect [40].

Radiotherapy

Both plaque brachytherapy and external beam radiotherapy (EBRT) have been employed for RCH in certain refractory cases. Indications for radiotherapy include tumors that cannot be directly treated with laser/cryopexy (e.g., juxtapapillary lesions encroaching on the optic nerve) or eyes with recurrent RCH activity after multiple treatments and larger tumors (thickness >3 mm) not suitable for other local therapies. Low-dose iodine-125 or Ru-106 plaque brachytherapy can be positioned over the tumor for a localized dose over a few days. Small series have shown that plaque radiotherapy can cause tumor regression, but it is associated with the risk of radiation retinopathy and papillopathy, especially for lesions near the optic disc or macula [41].

EBRT or proton beam can be used for diffuse or multiple RCHs but similarly carry significant side effects. Historically, radiotherapy has been a last resort, and some cases of diffuse bilateral RCH (in VHL patients) were managed with low-dose EBRT when other treatments failed [32].

Vitreoretinal Surgery

In selected cases with significant epiretinal membrane or advanced cases where RCH has led to tractional or exudative RD or, rarely, dense vitreous hemorrhage, vitreoretinal surgery is indicated. PPV with membrane peeling, often combined with scleral buckling, can reattach the retina by relieving the traction. Often, the surgeon will perform an endolaser photocoagulation or even an endoresection of the tumor during PPV, sometimes combined with retinectomy of the involved retinal area [42, 43].

Surgical series are small, given the rarity of such advanced presentations [44, 45]. A retrospective study of 16 eyes with complex RCH (most with RD) reported that PPV achieved complete retinal reattachment in the majority of eyes and local tumor control in all cases [46] (when combined with adjunct treatments), but limited visual function was achieved. van Overdam and colleagues [47] reported the results of early surgical intervention before the development of major complications in four cases. They advocated complete ligation of feeder and draining vessels, as well as complete removal of vitreous remnants and epiretinal membranes to prevent PVR. In their second report after 10 years of follow-up, all cases were stable. One eye experienced RD due to a new retinal hemangioblastoma and PVR formation. Another eye required a second surgery to perform membranectomy, thereby preventing RD [48]. In a retrospective report of PPV for RD due to RCH, the eyes with tractional detachment gained significant visual improvement. Eyes with exudative detachment or those with central tumors for which complete resection was not amenable did not achieve visual improvement [49]. Performing PPV, endodiathermy of feeding and draining vessels, endoresection of RCH, and silicone oil injection, Karacorlu et al. [50] achieved visual improvement and an anatomical success rate of 92% in 13 eyes. None of the tumors in their series were closer than 10 mm to the optic nerve or fovea.

Combination Therapies

The combination of traditional therapies, such as laser photocoagulation or cryotherapy with anti-VEGF agents or with systemic therapies, is promising in improving the outcomes of patients with RCH. For example, the use of anti-VEGF injections combined with laser therapy or cryotherapy reduces tumor secretion and size with visual improvement [51, 52]. Intravitreal or periocular steroids such as triamcinolone are used adjunctively to manage treatment-induced inflammation or persistent exudative macular edema [53]. More research is needed to optimize hybrid diets and assess their long-term effectiveness.

Recent Advancements

Improving imaging technologies and exploring molecular and genetic interventions are among the recent advances in understanding and managing RCH. The aim of focusing on new therapeutic approaches was to optimize treatment outcomes and minimize the risk of vision-threatening complications.

Novel Therapeutic Approaches

HIF Inhibitors

HIF inhibitors have recently emerged as a potential treatment option for RCH. These agents suppress the expression of angiogenic factors such as VEGF and PDGF by targeting the HIF pathway.

A case series of 7 VHL patients (12 eyes) treated with belzutifan found that all eyes with active RCHs achieved ocular tumor control over an average 13-month follow-up [54]. A subgroup analysis of LITESPARK-004 study, evaluated the efficacy of belzutifan in retinal hemangioblastoma as a secondary endpoint. Including 16 eyes with a median follow-up of 37.3 months, the response rate of all the lesions was graded as improved. A reduction of tumor mean area by 15% by month 12, and 30% by month 24, was observed in the subgroup of larger tumors [9]. However, the FDA has not approved belzutifan for RCH. Belzutifan (Welireg, Merck), the first FDA-approved HIF-2α inhibitor, is indicated for VHL-associated RCC, CNS hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery, but not for RCH [55].

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (e.g., sunitinib, pazopanib), target VEGF receptors and other pro-angiogenic pathways, inhibiting tumor growth and reducing exudation. They have shown promise in the treatment of RCH. In one pilot study, 3 patients with VHL-related juxtapupillary hemangioblastomas were treated with sunitinib, resulting in reduced macular edema and stabilization of vision in all cases despite no reduction in tumor size [56].

Epigenetic and Gene-Based Therapies

Epigenetic dysregulation (DNA methylation, histone acetylation) may contribute to VHL gene silencing and is a research target [57]. Gene therapy to restore functional VHL protein or CRISPR/Cas9-mediated mutation correction is theoretically promising but limited by the need for near-100% transfection efficiency in a tumor-suppressor context. Ocular gene therapy successes in inherited retinal dystrophies provide a framework [58, 59]. Table 1 summarizes the traditional and emerging treatment approaches for the management of RCH.

Table 1.

Current treatment options for the management of RCH

Treatment	Indications	Efficacy	Risks
Observation	Small peripheral RCH	Stable short-term	Progression
Laser photocoagulation	Small-medium RCH	High (97–100%)	Retinal damage
Cryotherapy	Medium-large RCH	High (67–94%)	Local inflammation/focal traction
Anti-VEGF therapy	Macular edema/exudation	Adjunctive (partial regression)	Repeated injections
Tyrosine kinase inhibitors	Juxtapapillary RCH	Reduction in macular exudation	Systemic adverse effects
Radiotherapy	Refractory juxtapapillary and large peripheral RCH	Moderate-high	Radiation retinopathy and papillopathy
Vitreoretinal surgery	RD/vitreous hemorrhage/epiretinal membrane/proliferative vitreoretinopathy	High anatomical success	Vitrectomy complications
Belzutifan (HIF-2α inhibitor)	Systemic treatment for multiple RCH	High systemic efficacy	Anemia/hypoxia
Steroids, intravitreal or sub-tenon injection	Exudative RD	Resorption of RD	Cataract, an increase in intraocular pressure

Artificial Intelligence in Diagnosis and Monitoring

The integration of artificial intelligence (AI) into ophthalmology has launched a new initiative to diagnose and monitor RCH and other retinal diseases. It helps with the early detection of RCH using AI algorithms, differentiation from other retinal vascular tumors, and prediction of disease progression in large data sets of retinal images. These tools have high potential in increasing diagnostic accuracy and simplifying patient management. Translating these discoveries into clinical practice requires the continued collaboration of ophthalmologists, researchers, and industry partners [60].

Discussion

Advanced imaging and targeted therapies have dramatically improved ocular survival and visual outcomes in RCH [61]. WF-FA remains the gold standard for detecting small peripheral RCH (<1 mm) not visible on clinical examination or OCTA [61]. High-resolution OCT and OCTA reveal subtle “flat” hemangioblastomas that evade routine examination [21]. Genetic testing is recommended for all RCH cases, especially in patients ≤30 years, where VHL prevalence is ∼45% versus 0.5% in those aged 61–70 years [5]. Therefore, genetic testing and medical workup for VHL should be considered in any patients with RCH, particularly in younger age groups.

Earlier diagnosis allows treatment of smaller tumors, enhancing success rates. RCH <1.5 mm achieves near-100% ablation with laser photocoagulation, compared to ∼73% for larger lesions requiring multiple sessions [32]. For juxtapapillary lesions, PDT is a viable option. In refractory cases or large tumors near the optic nerve, brachytherapy can be applied. For extrapapillary tumors posterior to the equator, PDT is still a good option, especially when local therapy with cryopexy is not amenable. Lesions anterior to the equator are usually treated with cryotherapy. Radiotherapy remains the last resort for larger refractory cases. Adjuvant therapy with steroid or anti-VEGF injections should be considered for exudative complications of the tumors. Recent advances herald promising treatment opportunities. Systemic HIF-2α inhibition with belzutifan marks a breakthrough. A 2024 multicenter trial reported 100% response, with >30% lesion area reduction by 24 months [9]. A companion case series confirmed control of all active RCH in 7 VHL patients (12 eyes), preventing blindness in high-risk optic disc tumors [54]. Optimal dosing and long-term data are pending. Consequently, modern strategies have reduced historical rates of enucleation/pre-phthisis (13%) and severe visual loss (31.9%), particularly in juxtapapillary or extensive cases [3]. Tyrosine kinase inhibitor and mammals of the rapamycin pathway (mTOR) are other future options. Given the role of the mTOR pathway in some retinal tumors (notably retinal astrocytic hamartomas in tuberous sclerosis), investigators have considered mTOR inhibition for RCH as well. The target of mTOR, which regulates cell growth and metabolism, plays a vital role in the development of tumors associated with VHL. mTOR signaling inhibition in preclinical models is a potential therapeutic target for RCH and is promising. Future research should prioritize randomized trials evaluating belzutifan integration with local therapies, AI-driven risk stratification, and CRISPR-based VHL correction to enable preventive, gene-level management.

Conclusion

RCH remains challenging, impacting vision and systemic health in VHL disease. Early diagnosis with advanced imaging and genetics, timely local therapy (laser/cryotherapy for small tumors; surgery for complications), and systemic HIF-2α inhibition for multifocal cases, delivered through multidisciplinary care, have shifted management from passive observation to proactive success.

Once leading to inevitable blindness, RCH now allows most patients to retain lifelong functional vision. Emerging gene therapy, molecular targeting, and AI promise even less invasive, personalized control, building on decades of clinical wisdom, and scientific innovation.

Statement of Ethics

During the preparation of this work, ChatGPT 4 was consulted regarding grammar, word choice, sentence structure, and overall clarity of expression. After using this service, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No finding was received for this article.

Author Contributions

Each author meets the ICMJE requirements for authorship. Supervision, conceptualization, methodology, and writing – review and editing: Masood Naseripour. Writing – original draft, data curation, and investigation: Kaveh Fadakar, Fatemeh Azimi, Mohammad Mahdi Taherian, Mahya Naseripour, and Reza Mirshahia.

Funding Statement

No finding was received for this article.